Perinatal outcomes of intrauterine fetal arrhythmias: A 10-year retrospective cohort study

Sustained fetal arrhythmia can produce life-threatening fetal distress, fetal hemodynamic compromise, hydrops fetalis, or even fetal death. Survivors may subsequently possess severe neurologic deficits. We conducted a retrospective observational study of pregnant women hospitalized with fetal arrhythmias from January 2011 to May 2020 at West China Second University Hospital, and fetal arrhythmias were diagnosed by specialists in cardiac ultrasonography. Of 90 cases of fetal arrhythmias, 14 (15.6%) were complicated by fetal congenital heart disease (CHD), 21 (23.33%) by fetal-hydrops, 15 (16.67%) cases by intrauterine therapy, and 6 (6.67%) by maternal auto-immune disease. In the fetal-hydrops group, the intrauterine therapy rate was significantly higher (47.62% vs 7.24%, P < .001) and the survival rate significantly lower (47.62% vs 92.75%, P < .001) than in the nonfetal hydrops group. A fetus whose arrhythmia was complicated by fetal-hydrops and CHD was delivered earlier and exhibited a lower cardiovascular profile score at diagnosis and birth, lower birth weight, and a higher rate of pregnancy termination than cases without hydrops and CHD (P < .05). Among the cases with maternal auto-immune disease, 71.43% (5/7) manifested fetal atrioventricular block. Multiple linear regression analysis revealed that 3 variables – fetal-hydrops (P < .001), body mass index (P = .014), and gestational age at diagnosis of fetal arrhythmia (P = .047) – were correlated with the gestational delivery age of arrhythmic fetuses. Parents should be counseled by the multidisciplinary team regarding the individualized management and prognosis of the arrhythmic fetus, and individualized fetal intrauterine therapy should be performed if necessary.


Introduction
The normal fetal heart rate is within the range of 110 to 160 bpm, and is considered abnormal if it is either outside this normal range or if the rhythm is irregular, and it can be classified into 3 categories: irregular arrhythmia, tachyarrhythmia, or bradycardia. [1,2] Fetal arrhythmia can also be classified as sustained or intermittent according to whether the arrhythmia was present for more than 50% [3,4] of the time during echocardiographic examination.
The clinical incidence of fetal arrhythmia is between 1% and 2%, [3,5] but the incidence in pregnant women at high risk is approximately 16.6% between 21 gestational weeks and full term. Sinus tachycardias and the most common fetal arrhythmia, premature atrial contraction (PAC), are both benign arrhythmias. [6] Despite the low clinical significance of PAC, approximately 1% of PAC cases are complicated by structural heart disease, and approximately 0.5% progress to supraventricular tachycardia (SVT). Sustained fetal arrhythmia can lead to fetal hemodynamic abnormalities that frequently result in fetal cardiac dysfunction, fetal-hydrops, fetal distress, or even fetal death. Arrhythmias that continue until the postnatal period and that demonstrate hemodynamic changes require intervention, [6] and it has been reported that 10% to 20% Medicine of cases referred to fetal cardiology specialists possess fetal arrhythmias. [7] During pregnancy, fetal arrhythmias are diagnosed by fetal echocardiography when abnormal auscultation of the fetal heart is detected at antenatal visits or during ultrasonographic examination. [1,8] The rate, duration, and origin of the rhythm and the degree of irregularity are often closely associated with the potential for hemodynamic consequences. [1] For example, the earlier the onset of tachycardia and the faster the ventricular rhythm, the more likely it is that fetal-hydrops will develop. [1] Surviving patients may also suffer severe neurologic deficits. [5,6] A ventricular rate < 55 bpm is now recognized to constitute a significant predictive risk factor for high mortality rate. [6] The trans-placental passage of maternal antiRo/antiLa antibodies generates passively acquired autoimmunity that may be associated with serious fetal complications, including inflammation, fibrosis, fetal auto-immune complete heart block, and calcification of the conduction system. [9,10] Although several authors have previously investigated fetal arrhythmias, few have reported on the outcomes of fetal arrhythmia during pregnancy or their long-term follow-up after birth. Hence, as preterm birth is the principal cause of neonatal death, [11] we herein performed a 10-year retrospective cohort study on pregnant women with fetal arrhythmias to establish which factors were associated with gestational age at delivery of babies with a prenatal diagnosis of fetal arrhythmia. We present the following article in accordance with the STROBE guidelines, propose a management strategy for this condition.

Study design and participants
We conducted an observational study of the retrospective cohort type of fetal arrythmia as presented in pregnant women who were hospitalized at the West China Second University Hospital between January 2011 and May 2020. This was not a screening study. Some patients underwent prenatal care at our hospital and some were referred from secondary local centers due to fetal arrhythmia. The inclusion criteria included hospitalized pregnant women whose fetus was diagnosed with arrhythmia via fetal echocardiography. The flow chart of this study is shown in Figure 1.

Fetal assessments
Fetal echocardiography was performed by cardiac ultrasound specialists when abnormal auscultation of the fetal heart was detected at antenatal visits or during ultrasonographic examination. [8,12] Fetal cardiac function was also assessed using the fetal cardiovascular profile score that encompassed fetal-hydrops, abnormal venous and arterial Doppler findings, cardiomegaly, atrioventricular valve regurgitation, and cardiac dysfunction; each component was scored 1 to 2 points according to ultrasonographic examination. [13] Fetal-hydrops was defined as the accumulation of abnormal fluid in at least 2 different fetal compartments, and included pleural effusion, pericardial effusion, and peritoneal effusion; skin edema (skin thickness > 5 mm); thickened placenta (≥4 cm in the second trimester or ≥ 6 cm in the third trimester); or polyhydramnios. [14,15] Fetal-hydrops was monitored every other 3-to-5-day period during pregnancy according to the intrauterine state of the arrhythmic fetus. [16]

Maternal assessments
Following a diagnosis of fetal arrhythmia, TORCH (toxoplasmosis, other [syphilis], rubella, cytomegalovirus, herpes simplex virus) and thyroid function were evaluated in maternal peripheral blood. Pregnant women with fetal arrhythmia were hospitalized so that they could be more closely observed for signs of fetal compromise or distress. Early delivery was considered and weighed against the complications of prematurity and fetal status in utero.

Intrauterine therapy
In cases requiring intrauterine treatment, pregnant women were evaluated by cardiac ultrasonography, electrocardiogram, cortisol assay, and levels of blood electrolytes before the initiation of drug treatment. The choice of trans-placental drugs was made by referring to the statement of the American Heart Association [16] : digoxin and sotalol were used in most tachycardia cases, while observation and internal treatment of maternal auto-immune diseases were implemented in irregular and bradycardia cases. During the administration of trans-placental drugs, fetal and maternal conditions were closely monitored. In addition, fetal echocardiography was performed every 5 to 7 days.

Data collection
We initially compiled data regarding fetal arrhythmia diagnosis, treatment, and maternal-neonatal outcomes. The collected data encompassed maternal complications, history of drug use during pregnancy, gestational age at fetal arrhythmia diagnosis, fetal intrauterine complications, fetal congenital heart disease (CHD), gestational age at delivery, admission to the NICU, neonatal conditions, and short-and long-term complications after birth.

Statistical analyses
The variables we examined included maternal age, body mass index (BMI), gravity, parity, intrahepatic cholestasis of pregnancy, gestational diabetes mellitus, hypothyroidism, gestational age when fetal arrhythmias were diagnosed, gestational age at birth, fetal-hydrops, fetal CHD, and birth weight. The primary outcome was survival of the arrhythmic fetus. Variables were analyzed by exploiting multiple linear regression; and chisquared, Mann-Whitney U, and Kruskal-Wallis H tests were applied where appropriate. P values < .05 were considered to be statistically significant. All statistical analyses were executed using SPSS (version 23

Results
We admitted 90 pregnant women with arrhythmic fetuses to our hospital between January of 2011 and May of 2020, detailed clinical reports were generated. The characteristic arrhythmias, associated fetal and maternal medical conditions, and pregnancy outcomes are described below.

Fetal arrhythmias in admitted pregnant women
Of the 90 cases of fetal arrhythmia, 5 had twin pregnancies: 3 dichorionic diamniotic (DCDA) twins, 1 case of monochorionic monoamniotic (MCMA) twins, and 1 case of monochorionic diamniotic (MCDA) twins (the demographic and obstetric characteristics of the admitted women are depicted in Table 1). Of the admitted patients, 14 (15.6%) cases were complicated by fetal CHD (these are displayed in Table 2), 21 (23.33%) by fetal-hydrops, 15 (16.67%) by intrauterine therapy, and 6 (6.67%) by maternal auto-immune disease. The types of fetal arrhythmias among the 90 cases are presented in Figure 1. Of the 5 twin pregnancies, 4 cases were complicated by 1 twin with arrhythmia with the co-twin normal (1 twin showed PAC in 1 monochorionic diamniotic twin pregnancy, 1 in dichorionic diamniotic twin (DCDA twin) pregnancy, and 1 in monochorionic monoamniotic twin pregnancy; and 1 twin manifested tachycardia in 1 DCDA twin pregnancy), and both twins were noted to have 1-degree atrioventricular block (AVB) in 1 DCDA twin pregnancy.
We collected the detailed data and information from the 90 cases. Thirteen cases ended in termination of the pregnancy; 2 cases underwent induced labor due to fetal death; and 75 cases resulted in live births, of which 74 newborns survived.

Perinatal outcomes of the fetal-hydrops and nonfetal hydrops groups.
Of the 90 cases, 21 cases were included in the fetal-hydrops group and 69 cases in the nonfetal hydrops group, depending on whether hydrops occurred during pregnancy.
Fetal death occurred in 2 cases, and 9 women chose to terminate their pregnancies. Ten women experienced live births, with a delivery age at 36.26 ± 1.77 (range, 33-38 +4 ) weeks of gestation, with a mean fetal CVPS of 8.63 ± 0.92 (range, 8-10) before birth. Mean birth weight was 2541.00 ± 890.53 (range, 1260-3420) g, with no cases demonstrating amniotic fluid turbidity. Four cases were transferred to the NICU. Ten newborns survived (1 case was a DCDA twin pregnancy), the outcomes were as follows. Three cases showed a restored sinus rhythm in utero; 1 case was treated with gamma globulin protein in the NICU and developed well at follow-up; 1 case was prescribed digoxin and sotalol for 6 months and was regularly visited by a pediatric cardiologist (the child is developing well, with no arrhythmic disease); 1 case had a restored sinus rhythm at 10 days of age; 1 case was prescribed propafenone and sotalol to control heart rhythm and was to undergo cardiac radiofrequency ablation at 3 years of age; and 3 cases required no regular pediatric care and developed well, with no arrhythmic disease at follow-up.

Age (yr)
Among the survivors, 18 cases were lost to long-term follow-up, while the remaining 46 cases were followed up by a pediatric cardiologist without issue. The long-term outcomes of the latter cases were as follows: 23 fetuses exhibited a restored sinus rhythm in utero; 1 fetus had a restored sinus rhythm before birth; 2 cases recovered heart rhythm at birth; 1 case was treated with metoprolol after birth and rhythm was restored at 8 months; 1 case is preparing to undergo surgery; 1 case underwent VSD surgery at 6 months, and sinus rhythm was successfully restored as a result; 1 case was lost to follow-up after discharge from the NICU; 1 case underwent cardiac surgery due to patent ductus arteriosus; 10 cases showed a restored sinus rhythm -3 cases at 1 month, 2 at 3 months, 1 at 5 months, 2 at 6 months, and 2 at 1 year each; and the remaining 5 cases did not require regular pediatric care and have all developed well, with no arrhythmic disease at follow-up.
The survival rate in the fetal-hydrops group was significantly lower than that in the fetal nonhydrops group (47.62% vs 92.75%, P = .000), and the rate of intrauterine therapy in the fetal-hydrops group was significantly higher than that in the fetal nonhydrops group (47.62% vs 7.24%, P = .000). The detailed data are shown in Table 3 and Figure 2.
There were 60 cases with no fetal-hydrops or CHD. The median gestational age at fetal arrhythmia diagnosis was 33 weeks (IQR, 27.15-35.22), the median CVPS at diagnosis was 10 (IQR, 9-10), the median gestational age at delivery was 39.14 weeks (IQR, 37.43-39.57), the median CVPS before birth was 9.5 (IQR, [9][10], and the median birth weight was 3240 g (IQR, 2712.50-3477.51 g). Four women (4.35%) chose TOP and 5 (7.25%) underwent intrauterine therapy. Fifty-six babies (81.86%) were born live and 19 cases (27.54%) were transferred to the NICU. All delivered babies survived and no neonatal deaths were noted at follow-up. Comparisons were statistically significant and details are shown in Table 4 and Figure 3. The gestational age at which fetal arrhythmia was diagnosed and babies delivered was earliest in the subgroup of fetal-hydrops with CHD (P = .032; P < .001), CVPS at diagnosis and before birth were the lowest in the subgroup of fetal-hydrops with CHD (P < .001 and P = .005), and birth weight was lowest in the subgroup of fetal-hydrops with CHD (P = .010). The TOP rate was significant as well at P < .001.

Maternal auto-immune disease, fetal arrhythmias, and perinatal outcomes.
Six of the 90 cases involved maternal auto-immune disease combined with fetal arrhythmia, 2 cases with connective tissue disease were treated with prednisone and hydroxychloroquine, 1 case with undifferentiated connective tissue disease did not receive medication, 1 case with systemic lupus erythematosus was treated with prednisone and hydroxychloroquine, and 2 cases had Sjögren syndrome (of whom only 1 case was treated with hydroxychloroquine and methylprednisolone). The types of fetal arrhythmias were as follows: 2 cases of third-degree AVB, 1 case of bradycardia, 1 case of sinoatrial block (SAB), 1 case of second-degree AVB, and 1 case of first-degree AVB in both twins of a DCDA pregnancy (the detailed information is available in Table 5).
In addition, 4 cases had no definitive diagnosis of auto-immune disease: 1 case of atrial flutter (AF) with positive nuclear antibodies, 2 cases of third-degree AVB with positive nuclear antibodies, and 1 case of PAC with positive antiSSB antibodies.
Complications associated with prematurity may result in neonatal morbidity and mortality, and thus the factors influencing gestational delivery age of arrhythmic fetuses constitutes an important issue. We conducted multiple linear regression to analyze the correlation between gestational age at delivery of arrhythmic fetuses and variables that included maternal age, BMI, gravidity, parity, intrahepatic cholestasis of pregnancy, gestational diabetes mellitus, hypothyroidism, maternal auto-immune disease, gestational age at fetal arrhythmia diagnosis, fetal-hydrops, and fetal CHD. The Durbin-Watson test value generated was 1.802, which verified that the research observations were independent of each other and that the regression model was statistically significant (F = 6.522, P < .001, adjusted R 2 = 0.411). The variables that correlated with gestational age at delivery of arrhythmic fetuses were fetal-hydrops (P < .001), BMI (P = .014), and gestational age at diagnosis of fetal arrhythmia (P = .047).

Discussion
In the present study, fetal PAC accounted for 52.22% (47/90) of the 90 fetal arrhythmia cases who were admitted to our hospital, confirming the findings of a previous study. [6] Of the 90 hospitalized patients, 15.56% (14/90) possessed fetal structural cardiac malformations as follows: 35.71% with VSD; 21.42% with atrial septal aneurysm; and the remainder with atrial septal defect (ASD), ductus arteriosus malformation, pulmonary artery valve stenosis, ectopic drainage of the superior vena cava, fetal univentricular heart and anomalous artery, and ductus arteriosus hemangioma. Consistent with previous studies, [3] we observed 1 case of fetal PAC with paroxysmal SVT, and 1 case of frequent fetal PAC that progressed to SVT and advanced to fetal tachycardia during intrauterine digoxin treatment. [3,7,8] Although the clinical outcome for PAC is better than that for other fetal arrhythmias, patients with PAC still require close observation to avoid adverse perinatal outcomes.
Fetal tachyarrhythmia refers to a fetal heartbeat > 180 bpm, has an incidence of 0.4% to 0.6%, and is most frequently observed in late pregnancy. [12,17] SVT and AF are the most Table 3 Demographic characteristics of groups with fetal-hydrops and nonfetal hydrops.

Fetal-hydrops
Nonfetal hydrops P  common fetal tachyarrhythmias, while other types such as fetal sinus tachycardia, atrial tachycardia, and junctional tachycardia can be caused by maternal fever or infection. [8] In our study, 22 cases of fetal tachyarrhythmia were diagnosed, but none was caused by maternal fever or infection. SVT was the most common tachyarrhythmia, accounting for 45.45% (10/22); and this was followed by tachycardia at 22.73% (5/22), AF at 18.18% (4/22), atrial fibrillation at 9.09% (2/22), and ventricular tachycardia at 4.55% (1/22). Fetal bradycardia can be secondary to intrauterine fetal distress, and is characterized by abnormal function of the sinoatrial node caused by auto-immune antibodies, an abnormal cardiac structure, and long Q-T syndrome. [1] In our study, 49 cases of fetal bradycardia were diagnosed in the outpatient department; of these, 32 presented with fetal AVB, 11 with fetal bradycardia, 5 with sinus bradycardia, and 1 with sinoatrial block.
Maternally administered trans-placental antiarrhythmics should be considered for improved perinatal outcomes. Carberry et al [18] reported that rhythm control was achieved in 76% of SVT cases. In a multicenter trial study, fetal tachyarrhythmia resolved in 89.8% of cases overall and in 75.0% of cases of fetal-hydrops after administration of protocol-defined trans-placental digoxin, sotalol, or flecainide. [19]  .000 Neonatal deaths, n (%) / 0 1 (11.11) 0 / CHD = congenital heart disease, CVPS = cardiovascular profile score, GA = gestational age, TOP = termination of pregnancy.

Fetal-hydrops and perinatal outcomes of fetal arrhythmias
The presence of fetal-hydrops is an important determinant of fetal outcome. [8,[14][15][16]20,21] Fetal-hydrops is defined as excessive extravascular fluid of the fetus, leading to extensive subcutaneous edema and fetal serous effusion. Fetal arrhythmia is a common cause of nonimmune fetal edema that refers specifically to cases that were not caused by red cell alloimmunization, with persistent SVT and AF as the most common signs. [14] It is estimated that 35% to 60% of fetal SVT cases are complicated by nonimmune fetal edema, which may then lead to nonimmune edema with a fetal mortality as high as 17%. [6,15] In the present study, among inpatients with nonimmune fetal edema, 28.57% (6/21) were complicated with AVB, 23.8% (5/21) with SVT, and 14.3% (3/21) with PAC; and the survival rate in the fetal-hydrops group was significantly lower than that in the fetal nonhydrops groups (47.62% vs 92.75%, P = .000). We therefore recommend identifying fetal edema as soon as possible in the perinatal period, and that the parents be counseled so as to arrive at a timely clinical decision. Nonimmune fetal edema induced by fetal arrhythmia should also be distinguished from immune fetal edema caused by other conditions. The Maternal-Fetal Medical Association Guidelines recommended that a fetus with nonimmune edema caused by fetal arrhythmia be delivered naturally at 34 weeks of gestation -if not at term -and that trans-placental drugs be used in the absence of maternal-fetal contraindications. [16] In our study, the delivery ages of the nonimmune fetal edema cases were 33, 33 +6 , 35 +4 , 36, 36 +1 , 36 +5 , 37 +2 , 37 +2 , 38 +1 , and 38 +4 weeks.

Fetal CHD and perinatal outcome of fetal arrhythmias
Several researchers have reported the outcomes of fetal arrhythmia combined with CHD. Wu et al reported 2 cases of fetal VSD with long Q-T syndrome, ventricular tachycardia, and AVB; their cases did not survive. [22] Furthermore, Rice et al noted that fetal atrial septal aneurysm was highly associated with fetal atrial arrhythmias (P < .001), [23] and Morales et al found upon ultrasonographic examination that PAC was readily engendered by an atrial septal aneurysm that squeezed the anterior wall of the atrium. [24] Moreover, some authors reported fetal ASD with complete atrioventricular canal defect, ectopic drainage of the pulmonary vein or vena cava, other cardiac structural malformations such as second-degree AV, [25] and fetal ASD with fetal bradycardia. [26] In the present study, we demonstrated similar findings in 14 cases of fetal heart malformations, of whom 42.86% (6/14) manifested fetal VSD complicated by premature ventricular contractions, atrial PAC with left atrial isomerism, third-degree AVB, and bradycardia. Three cases of fetal arrhythmia were complicated by fetal atrial septal aneurysm, 1 of whom showed PAC; and 2 cases of ASD were also complicated by PAC and AF.
Giorgione et al [27] ascertained that fetuses conceived via in vitro fertilization and embryo transfer were at a significantly greater risk of fetal CHD. In our study, 11.76% (12/102) of the admitted women were pregnant by in vitro fertilization and embryo transfer and 1 case was complicated by fetal atrial septal aneurysm, consistent with the findings of the Giorgione group (8.3% vs 15.56%, P = .000).
We observed 7 cases of fetal arrhythmias with positive maternal autoantibodies, with 2 cases (2/6, 33.33%) being third-degree AVB -a higher prevalence than that reported previously. [28] The fetal arrhythmias in our study were detected at 21 to 25 +2 weeks of gestation. Complete heart block occurring earlier than after 16 weeks in antiRo-La patients is rare, and this finding was congruent with previously published reports. [9,10] Auto-immune diseases such as maternal lupus correlate with complete fetal AVB. Although the incidence of positive maternal autoantibodies with fetal AVB and the effects on perinatal outcome require further study, the diagnosis of fetal AVB should be followed by close monitoring of maternal autoantibodies in order to determine the corresponding maternal and fetal treatments needed to improve fetal outcome. [1] It is essential to improve the survival rate of fetuses with arrhythmia and reduce the associated complications. In this study, multiple linear regression analysis revealed that fetal-hydrops, BMI, and the gestational age at fetal arrhythmia diagnosis were statistically significant independent variables of the gestational age at delivery.

Strength and limitations
For this study we collected 90 cases of fetal arrhythmia from a single center over a 10-year period, and compared fetal arrhythmia cases in fetal CHD and nonfetal CHD groups and between fetal-hydrops and nonfetal hydrops groups. The long-term outcomes of the arrhythmic fetuses after birth were followed, fetal arrhythmia and its associated maternal and fetal factors were analyzed. Our results suggest that fetal-hydrops, and body mass index, and gestational age at diagnosis of fetal arrhythmia were correlated with the gestational delivery age of arrhythmic fetuses.
The limitations to this study lay primarily in its retrospective nature and the fact that some women chose to terminate their pregnancies or declined follow-up regarding the long-term outcomes of the infants.

Conclusions
Based upon previous data and the findings of the current study, the outcomes of arrhythmic fetuses were affected by fetal CHD, fetal-hydrops, and maternal complications (particularly auto-immune diseases). Once fetal arrhythmias are diagnosed, we recommend that parents be counseled by the multidisciplinary team as to the individualized management and prognosis regarding the fetus. If necessary, individualized fetal intrauterine therapy should commence so as to improve the perinatal and long-term outcomes. Close perinatal management should also be undertaken by clinicians in cases showing both fetal-hydrops and fetal CHD.
Our study findings contribute to our understanding of the decisive risk factors in fetal arrhythmia cases, may assist clinicians in fetal maternal medicine and fetal cardiovascular fields in decision-making in the management of fetal arrhythmias. Further research with a larger number of cases, however, is necessary to determine the relationship between the outcomes and other clinical parameters. We posit that this will facilitate the establishment of more beneficial management regimens for fetal arrhythmia.